Biomed & Pharmacother(l990) 44.511-514 0 Elsevier, Paris
era D Koutsikos, B Agroyannis, H Tzanatos-Exarchou University of Athens, Nephrological Center, Aretaieon University Hospital, 76, Vasilissis Sofas Ave Athens 11528, Greece (Received 5 December 1988; accepted 22 October 1990)
Summary - Biotin in high doses was given for l-2 years to three diabetic patients suffering from severe diabetic peripheral neuropathy. Within 4-8 weeks there was a marked improvement in clinical and laboratory findings. It is suggested that in diabetes may exist a deficiency, inactivity or unavailability of Biotin; resulting in disordered activity of biotindcpendent enzyme, pyruvate carboxylase. leading to accumulation of pyruvate and/or depletion of aspartate. both of which play a significant role in nervous system metabolism. Based on our good results, regular biotin administration could be suggested for every diabetic patient for the prevention and management of peripheral neuropathy although extensive random&d clinical trials are required.
biotin / diabetes melitus I diabetic peripheral qeuropathy REsum6 - Ikaitement de la neuropatbie pkiphkrique diabktique par la biotine. On a admittistrk pendant 1-2 ans de fortes doses de biotine ci trois patients diabktiques. atteints d’une s&v&e neuropathie pkripurique. Une nette am&oration clinique et biologique ci tte’ constate’e au tours des 4-8 premihres semaines du traitement. I1 est suggtW que I’itat diabktique est accompagni d’une insuffisance ou d’une inactivitt! de biotine. entrabtant une diminution de I’activitk de I’enzyme d& pendant de la biotine. la carboxylase pyruvique. qui conduit 0 une accumulation de pyruvate etlou une diminution de l’aspartate, les &ux jouant un rale important dons le m&abolisme du systtime nerveux. Ces r&ultats encourageants nous am&tent ci penser que I’administration rigulike de biotine serait bb&ique pour les malades diabitiques, rant pour la pr&ention que pour le traitement de la neuropathie ptkiphbrque. Des essais cliniques randomis& sur un pIus grand nombre de malades sont bien siir ne’cessaires. biotine I diabkte melitus I neuropathie pdriphkrique diabetique
Introduction The long experience (up to ten years) of our Center in the effective management of uremic peripheral neuropathy using large doses of biotin [20, 211, the known absence of toxicity of biotin 121, the clinical and pathologic similarities of diabetic and uremic neuropathy [lS], the suggestion of abnormally bound and biologically unavailable biotin [6] and the disordered pyruvate metabolism in diabetics [19], prompted us to use biotin in three patients suffering from severe diabetic peripheral neuropathy complicating long-standing diabetes mellitus.
The patients were three males aged 67 (1). 54 (2) and 39 (3) years-old, known to be diabetic for 27, 14 and 22 years respectively. Two of them (1 and 2) were overweight and all three had been treated for the last 12,3 and 24 years respectively with insulin, in doses sufficient to keep fasting blood glucose levels between 6.5 to 7.8 mmol/L in serial measurements. All patients complained of painful muscle cramps in the lower limbs, restless leg syndrome, paresthesias, difficulties in standing for long periods and inability to ascend stains and to walk unassisted for more than 150,250 and 100 meters respectively. Upon clinical examination, the tendon reflexes in patient 1 were found to be abolished in the legs and
512
D Koutsikos et al
weak in the upper limbs; in patient 2 weak in both upper and lower limbs, aud in patient 3 abolished in both upper and lower limbs. All three patients were found to hsvc sensory disturbances in pain and tempersttne perception over the distal one-third (patients 1 and 2) and One half (patient 3) of the lower limbs. Seas0t-y disturbances of the upper limbs were noted Only in patient 3, less severe compared to the lower limbs. Clinically evident autonomic neurologic disturbances were only present in patient 3. Motor nerve conduction velocity (MNCV) in the peroneal nerve was 3lms-’ (l), 35ms-’ (2) and 23ms-’ (normal 4Oms-‘) and the sural nerve sensory action potential (SAP) was 3.2 PV (l), 3.8 PV (2) and 2.7 PV (3) (figs 1 and 2) None of the patients suffered from chronic renal failure, alcoholism or other conditions known to cause peripheral neuropathy. The patients were given biotin in the following scheme: 10 mg daily intramuscularly (IM) for 6 weeks, 10 mg IM 3 times per week, also for 6 weeks and 5 mg orally per day to the present date, 130,116 and 64 weeks in patients 1,2 and 3 respectively. These biotin doses are 5&100-fold of the daily requirements, as had been suggested for other pathologic conditions [2]. previous treatment and diet were maintained almost unaltered except for antihypertensives and antibiotics, when required. During observation the patients received various types of vitamins. The patients were reviewed clinically every 4 weeks for the first 6 months and every 12 weeks thereafter. Motor nerve conduction velocity and sensory nerve
action potential studies were carried out 6.12 and 24 months after commencement of biotin treatment.
Within 4-8 weeks following biotin administration, a marked objective improvement of symptoms was observed, namely painful muscle cramps, paresthesias, the ability to stand, walk and ascend stairs and the disappearance of restless leg syndrome in all three patients. After 1 year of treatment with biotin, all patients were free of paresthesias and could walk more than 300 meters unassisted. The tendon reflexes in patient 1 increased gradually in the upper limbs but remained unaltered in the lower limbs. Patient 2 became almost normal over a period of six months and remained stable thereafter in both upper and lower limbs. In patient 3, tendon reflexes remained absent in both limbs. The sense in pain and temperature perception improved in all three patients although more significantly in patients 1 and 2.
In patients 1 and 2 there was a slight improvement in motor nerve conduction velocity (MNCV) in peroneal nerve (32.6 ms-’ and 36.4 msB1 respectively) and the sural nerve sensory action potential (SAP) (4.1 pV and 4.4 pV respectively), which was more prominent after one year (35.2 ms-’ and 38.1 ms-l for MNCV and 4.7 yV and 5.3 pV for SAP). This improvement remained practically unchanged after two years (35.6 ms-‘, 36.7 ms-t for MNCV and 4.6 pV, 5.4 pV for SAP). In patient 3, MNCV and SAP remained unchanged after 6 months and one year (23 ms-‘, 24 ms-’ and 2.7 pV, 2.5 pV respectively) (figs 1 and 2). 40
0 0
6
12
24
lime, months Fig 1. Changes of Motor Nerve Conduction Velocity (MNCV) in peroneal nerve fnllowing 6. 12 and 24 months of Biotin administra:ion in three patients with severe diabetic peripheral neuropathy.
J Of
r
Biotin administration
I
0
I
I 6
I
I 12
I
I 24
Time, months Fig 2. Changes of Sensory Action Potential (SAP) in surai nerve following 6.12 and 24 months of Biotin administration in three patients with severe diabetic peripheral neuropathy.
Biotin for diabetic peripheral neu~pathy No significant changes of fasting blood sugar levels were noted in any of the patients being treated with the same insulin doses, The aetiology of diabetic peripheral neuropathy remains obscure [9]; several factors have been incriminated, relating to metabolic abnormalities of persistent hyperglycemia [3, 14, 181, namely the accumulation of sorbitol in nerve tissue due to activation of the polyol-pathway through the enzyme aldose reductase and the inhibition of myo-inositol uptake by the nerve, resulting in depletion of nerve myo-inositol [lo, 17, 221. In one recent study, nerve myo-inositol levels were normal in diabetics with neuropathy [8], a finding that goes against the theory of the role of myo-inositol depletion. Ischemic changes of nerves due to impa~ent of vasa nervorum and endothelial matrix has been supported by recent autopsy studies [4, 7, Ill. A disorder of pyruvate metabolism has been described in diabetes but the authors failed to find any difference between patients with and without peripheral neuropathy [ 191. In a study of insulin-dependent diabetic patients it was observed that the administration of high doses of biotin (16 mg daily) resulted in a fall of fasting blood glucose levels and that the epithelial tissue biotin levels were higher compared to normal subjects while the plasma biotin leveis were similar in the two groups. Based on these observations the authors suggested that in diabetic patients there may be an abnormal binding of biotin thus making it biologically unavailable [6]. Biotin is a prosthetic group (co-enz~e} of the enzyme pyruvate carboxylase which plays a cardinal role in gluconeogenesis, promoting the further metabolism of pyruvate and oxaloacetate, known to be an essential process for fixing carbon dioxide in the brain [ 131 and the de now synthesis of aspartate, known to be a neurotransmiter Dl* A condition of deficiency, inactivity or unavailability of biotin could decrease or exclude the activity of biotin-dependent enzyme pyruvate carboxylase, resulting in pyruvate accumulation as was described in diabetics [ 193 and/or aspartate depletion, with possible effects on the nervous system. Supporting this hypothesis is the impairment of the nervous system seen in necrotizing encephalomyopathy (Leiner’s disease) which is suggested to be the result of accumulation of pYruvate and lactate due to the absence or very low
513
activity of the biotin-dependent pyruvate carboxylase [l, 21. The early observation of disordered pyruvate metabolism 1191 and the suggestion of abnormal binding and/or biological unav~a~~~ of biotin in diabetics [61, the known key role of biotin, as a co-enzyme, in pyruvate carboxylase activity which is involved in the nervous system metabolism, [l, 21 suggests that biotin plays a role in the impairment of nerves in diabetics through pyruvate accumulation and/or aspartate depletion in combination with other mech~isms [3, 4, 7, 8, 10, 11, 14, 17, 18, 223. Low biotin blood levels are observed in a high proportion of patients suffering from several conditions affecting peripheral nerve function such as alcoholics 121and epileptics undergoing treatment
WI. Up to now, there is no effective treatment for diabetic peripheral neuropathy; amelioration has been observed following administration of aldose reductase inhibitors [lo, 16, 221 and intensive control of blood glucose with continuous insulin infusion f14]. The good therapeutic results obtained in our two patients (1 and 2), being stable after more than two years and the slight to moderate clinical improvement of the third patient, also stable for more than one year, indicates a beneficial role of biotin adminis~ation in diabetic pe~pher~ neuropathy. The observation of the lack of laboratory improvement in patient 3 with the most severe neuropathy compared to patients 1 and 2, indicates that biotin is more efficient in the early stages of this complication. Based on our results, biotin in high doses seems to have a beneficial therapeutic role, especially in the early stages of diabetic peripheral neuropathy and could be administered to every diabetic patient, given that a) biotin in such doses is free of any toxicity [2] and 6) that evidence of abnormal peripheral nerve function can be found in nearly all diabetic patients 113, 141. Randomised extensive clinical and pathologic trials are however required.
1 Achuta-Murhty PN, Mistry SP (1977) Biotiu. Proc FD Nutr Sci 2, 405 2 Bonjour JP (1984) Biotin. In: Muchh. fh~tf~~~~ caf vitamins. Dekker, New York, p 403
514
D Koutsikos et al
3 Braun MJ, Asbmy AK (1984) Diabetic neuropathy. Ann Nettrol 15, 2 4 Brownlee M, Gerami A, Vlassara H (1988) Advanced glucosylation end products in tissue and the biochemical basis of diabetic complications. N En& J Med 318, 1315 5 Clements RS Jr (1979) Diabetic neuropathy-new concepts of its etiology. Diabetes 28, 604 6 Coggeshall JC, Heggers JP, Robson MC, Baker H (1985) Biotin status and plasma glycose in diabetics. Ann NY Acad Sci 447, 389 7 Dyck PJ, Kames JL, O’Brien P, Okazaki H, Lais A, Engelstad J (1986) The spatial distribution of fiber loss in diabetic polyneuropathy suggest ischemia. Ann New-01 19, 440 8 Dyck PJ, Zimmerman BR, Villen TH. Minnerath SR, Kames JL, Yao JK, Poduslo JF (1988) Nerve glucose, fructose, sorbitol, myo-inositol and fiber degeneration and regeneration in diabetic neuropathy. N Engl .I Med 319, 542 9 Asbury AK (1988) Understanding diabetic neuropathy. N Engl J Med 319, 577 10 Greene DA, Latimer SA, Sima AAF (1987) Sorbitol, Phosphoionositides and Sodium-Potasium ATPase in the pathogenesis of diabetic complications. N Engl J Med 316, 599 11 Johnson PC, Doll SC, Cromey DW (1986) Pathogenesis of diabetic neuropathy; Ann Neural 19, 450 12 Krausse K-H, Bonjour J-P, Berlit P, Kohen W (1985) Biotin status in epileptics. Ann NY Acad Sci 447, 297 13 Pate1 MS (1974) The relative significance of COsfixing enzymes in the metabolism of rat brain. J Neurochem 22, 717 14 Porte D Jr, Graf RI, Haltez JB, Pfeifer MA, Halar E (1981) Diabetic neuropathy and plasma glucose control. Am J Med 70, 195
15 Said G, Slama G, Silva J (1983) Progressive centripetal degeneration of axons in small fibre diabetic polyneuropathy. A clinical and pathological study. Brain 106, 791 16 Sima AAF, Bril V, Nathaniel V, Thomas AJ, McEven MS, Brown MB, Lattimer SA, Greene DA (1988) Regeneration and repair of myelinated fibers in sural-nerve biopsy specimens from patients with diabetic neuropathy treated with sorbinil. N EngI J Med 319, 548 17 Sima AAF, Nathaniel V, Bril V, Even TAJ, Greene DA (1988) Histopathological heterogeneity of neuropathy in insulin dependent and non-insulin-dependent diabetics and demonstration of axo-glial dysfunction in human diabetic neuropathy. J Clin Invest 81, 349 18 Thomas PK, Eliason S (1984) Diabetic neuropathy. In: Peripheral neuroparhy. (Dyck PJ, Thomas PK, Lambert EH, Bunge RP, eds) 2nd Ed. Philadelphia: WB Saunders, I 773 19 Thomson PHS, Butterfield WJH, Fry IK (1960) Pyruvate metabolism in diabetic neuropathy. Proc R Sot Med 53, 143 20 Yatzidis H, Koutsikos D, AgI’OyaMiS B, Papastephanidis C, Frances-Plemenos M, Delatola Z (1984) Biotin in the management of Uremic neurologic disorders. Nephron 36, 183 21 Yatzidis H, Koutsikos D, Alaveras AG, Papastephanidis C, Francos-Plemenos M (1981) Biotin for neurologic disorders of uremia. N Eng J Med 305, 764 22 Zundzewitsch RG, Jaspan JB, Polonsky KS, Weinberg GR, Halter JS, Halar E, Pfeifer M, Vukadinovic C, Bernstein L, Schneider M, Liang K, Cabbay KH, Rubinstein AH, Porte D (1983) Aldose reductase inhibition improves nerve conduction velocity in diabetic patients. N Engl J Med 308, 119
era D Koutsikos, B Agroyannis, H Tzanatos-Exarchou University of Athens, Nephrological Center, Aretaieon University Hospital, 76, Vasilissis Sofas Ave Athens 11528, Greece (Received 5 December 1988; accepted 22 October 1990)
Summary - Biotin in high doses was given for l-2 years to three diabetic patients suffering from severe diabetic peripheral neuropathy. Within 4-8 weeks there was a marked improvement in clinical and laboratory findings. It is suggested that in diabetes may exist a deficiency, inactivity or unavailability of Biotin; resulting in disordered activity of biotindcpendent enzyme, pyruvate carboxylase. leading to accumulation of pyruvate and/or depletion of aspartate. both of which play a significant role in nervous system metabolism. Based on our good results, regular biotin administration could be suggested for every diabetic patient for the prevention and management of peripheral neuropathy although extensive random&d clinical trials are required.
biotin / diabetes melitus I diabetic peripheral qeuropathy REsum6 - Ikaitement de la neuropatbie pkiphkrique diabktique par la biotine. On a admittistrk pendant 1-2 ans de fortes doses de biotine ci trois patients diabktiques. atteints d’une s&v&e neuropathie pkripurique. Une nette am&oration clinique et biologique ci tte’ constate’e au tours des 4-8 premihres semaines du traitement. I1 est suggtW que I’itat diabktique est accompagni d’une insuffisance ou d’une inactivitt! de biotine. entrabtant une diminution de I’activitk de I’enzyme d& pendant de la biotine. la carboxylase pyruvique. qui conduit 0 une accumulation de pyruvate etlou une diminution de l’aspartate, les &ux jouant un rale important dons le m&abolisme du systtime nerveux. Ces r&ultats encourageants nous am&tent ci penser que I’administration rigulike de biotine serait bb&ique pour les malades diabitiques, rant pour la pr&ention que pour le traitement de la neuropathie ptkiphbrque. Des essais cliniques randomis& sur un pIus grand nombre de malades sont bien siir ne’cessaires. biotine I diabkte melitus I neuropathie pdriphkrique diabetique
Introduction The long experience (up to ten years) of our Center in the effective management of uremic peripheral neuropathy using large doses of biotin [20, 211, the known absence of toxicity of biotin 121, the clinical and pathologic similarities of diabetic and uremic neuropathy [lS], the suggestion of abnormally bound and biologically unavailable biotin [6] and the disordered pyruvate metabolism in diabetics [19], prompted us to use biotin in three patients suffering from severe diabetic peripheral neuropathy complicating long-standing diabetes mellitus.
The patients were three males aged 67 (1). 54 (2) and 39 (3) years-old, known to be diabetic for 27, 14 and 22 years respectively. Two of them (1 and 2) were overweight and all three had been treated for the last 12,3 and 24 years respectively with insulin, in doses sufficient to keep fasting blood glucose levels between 6.5 to 7.8 mmol/L in serial measurements. All patients complained of painful muscle cramps in the lower limbs, restless leg syndrome, paresthesias, difficulties in standing for long periods and inability to ascend stains and to walk unassisted for more than 150,250 and 100 meters respectively. Upon clinical examination, the tendon reflexes in patient 1 were found to be abolished in the legs and
512
D Koutsikos et al
weak in the upper limbs; in patient 2 weak in both upper and lower limbs, aud in patient 3 abolished in both upper and lower limbs. All three patients were found to hsvc sensory disturbances in pain and tempersttne perception over the distal one-third (patients 1 and 2) and One half (patient 3) of the lower limbs. Seas0t-y disturbances of the upper limbs were noted Only in patient 3, less severe compared to the lower limbs. Clinically evident autonomic neurologic disturbances were only present in patient 3. Motor nerve conduction velocity (MNCV) in the peroneal nerve was 3lms-’ (l), 35ms-’ (2) and 23ms-’ (normal 4Oms-‘) and the sural nerve sensory action potential (SAP) was 3.2 PV (l), 3.8 PV (2) and 2.7 PV (3) (figs 1 and 2) None of the patients suffered from chronic renal failure, alcoholism or other conditions known to cause peripheral neuropathy. The patients were given biotin in the following scheme: 10 mg daily intramuscularly (IM) for 6 weeks, 10 mg IM 3 times per week, also for 6 weeks and 5 mg orally per day to the present date, 130,116 and 64 weeks in patients 1,2 and 3 respectively. These biotin doses are 5&100-fold of the daily requirements, as had been suggested for other pathologic conditions [2]. previous treatment and diet were maintained almost unaltered except for antihypertensives and antibiotics, when required. During observation the patients received various types of vitamins. The patients were reviewed clinically every 4 weeks for the first 6 months and every 12 weeks thereafter. Motor nerve conduction velocity and sensory nerve
action potential studies were carried out 6.12 and 24 months after commencement of biotin treatment.
Within 4-8 weeks following biotin administration, a marked objective improvement of symptoms was observed, namely painful muscle cramps, paresthesias, the ability to stand, walk and ascend stairs and the disappearance of restless leg syndrome in all three patients. After 1 year of treatment with biotin, all patients were free of paresthesias and could walk more than 300 meters unassisted. The tendon reflexes in patient 1 increased gradually in the upper limbs but remained unaltered in the lower limbs. Patient 2 became almost normal over a period of six months and remained stable thereafter in both upper and lower limbs. In patient 3, tendon reflexes remained absent in both limbs. The sense in pain and temperature perception improved in all three patients although more significantly in patients 1 and 2.
In patients 1 and 2 there was a slight improvement in motor nerve conduction velocity (MNCV) in peroneal nerve (32.6 ms-’ and 36.4 msB1 respectively) and the sural nerve sensory action potential (SAP) (4.1 pV and 4.4 pV respectively), which was more prominent after one year (35.2 ms-’ and 38.1 ms-l for MNCV and 4.7 yV and 5.3 pV for SAP). This improvement remained practically unchanged after two years (35.6 ms-‘, 36.7 ms-t for MNCV and 4.6 pV, 5.4 pV for SAP). In patient 3, MNCV and SAP remained unchanged after 6 months and one year (23 ms-‘, 24 ms-’ and 2.7 pV, 2.5 pV respectively) (figs 1 and 2). 40
0 0
6
12
24
lime, months Fig 1. Changes of Motor Nerve Conduction Velocity (MNCV) in peroneal nerve fnllowing 6. 12 and 24 months of Biotin administra:ion in three patients with severe diabetic peripheral neuropathy.
J Of
r
Biotin administration
I
0
I
I 6
I
I 12
I
I 24
Time, months Fig 2. Changes of Sensory Action Potential (SAP) in surai nerve following 6.12 and 24 months of Biotin administration in three patients with severe diabetic peripheral neuropathy.
Biotin for diabetic peripheral neu~pathy No significant changes of fasting blood sugar levels were noted in any of the patients being treated with the same insulin doses, The aetiology of diabetic peripheral neuropathy remains obscure [9]; several factors have been incriminated, relating to metabolic abnormalities of persistent hyperglycemia [3, 14, 181, namely the accumulation of sorbitol in nerve tissue due to activation of the polyol-pathway through the enzyme aldose reductase and the inhibition of myo-inositol uptake by the nerve, resulting in depletion of nerve myo-inositol [lo, 17, 221. In one recent study, nerve myo-inositol levels were normal in diabetics with neuropathy [8], a finding that goes against the theory of the role of myo-inositol depletion. Ischemic changes of nerves due to impa~ent of vasa nervorum and endothelial matrix has been supported by recent autopsy studies [4, 7, Ill. A disorder of pyruvate metabolism has been described in diabetes but the authors failed to find any difference between patients with and without peripheral neuropathy [ 191. In a study of insulin-dependent diabetic patients it was observed that the administration of high doses of biotin (16 mg daily) resulted in a fall of fasting blood glucose levels and that the epithelial tissue biotin levels were higher compared to normal subjects while the plasma biotin leveis were similar in the two groups. Based on these observations the authors suggested that in diabetic patients there may be an abnormal binding of biotin thus making it biologically unavailable [6]. Biotin is a prosthetic group (co-enz~e} of the enzyme pyruvate carboxylase which plays a cardinal role in gluconeogenesis, promoting the further metabolism of pyruvate and oxaloacetate, known to be an essential process for fixing carbon dioxide in the brain [ 131 and the de now synthesis of aspartate, known to be a neurotransmiter Dl* A condition of deficiency, inactivity or unavailability of biotin could decrease or exclude the activity of biotin-dependent enzyme pyruvate carboxylase, resulting in pyruvate accumulation as was described in diabetics [ 193 and/or aspartate depletion, with possible effects on the nervous system. Supporting this hypothesis is the impairment of the nervous system seen in necrotizing encephalomyopathy (Leiner’s disease) which is suggested to be the result of accumulation of pYruvate and lactate due to the absence or very low
513
activity of the biotin-dependent pyruvate carboxylase [l, 21. The early observation of disordered pyruvate metabolism 1191 and the suggestion of abnormal binding and/or biological unav~a~~~ of biotin in diabetics [61, the known key role of biotin, as a co-enzyme, in pyruvate carboxylase activity which is involved in the nervous system metabolism, [l, 21 suggests that biotin plays a role in the impairment of nerves in diabetics through pyruvate accumulation and/or aspartate depletion in combination with other mech~isms [3, 4, 7, 8, 10, 11, 14, 17, 18, 223. Low biotin blood levels are observed in a high proportion of patients suffering from several conditions affecting peripheral nerve function such as alcoholics 121and epileptics undergoing treatment
WI. Up to now, there is no effective treatment for diabetic peripheral neuropathy; amelioration has been observed following administration of aldose reductase inhibitors [lo, 16, 221 and intensive control of blood glucose with continuous insulin infusion f14]. The good therapeutic results obtained in our two patients (1 and 2), being stable after more than two years and the slight to moderate clinical improvement of the third patient, also stable for more than one year, indicates a beneficial role of biotin adminis~ation in diabetic pe~pher~ neuropathy. The observation of the lack of laboratory improvement in patient 3 with the most severe neuropathy compared to patients 1 and 2, indicates that biotin is more efficient in the early stages of this complication. Based on our results, biotin in high doses seems to have a beneficial therapeutic role, especially in the early stages of diabetic peripheral neuropathy and could be administered to every diabetic patient, given that a) biotin in such doses is free of any toxicity [2] and 6) that evidence of abnormal peripheral nerve function can be found in nearly all diabetic patients 113, 141. Randomised extensive clinical and pathologic trials are however required.
1 Achuta-Murhty PN, Mistry SP (1977) Biotiu. Proc FD Nutr Sci 2, 405 2 Bonjour JP (1984) Biotin. In: Muchh. fh~tf~~~~ caf vitamins. Dekker, New York, p 403
514
D Koutsikos et al
3 Braun MJ, Asbmy AK (1984) Diabetic neuropathy. Ann Nettrol 15, 2 4 Brownlee M, Gerami A, Vlassara H (1988) Advanced glucosylation end products in tissue and the biochemical basis of diabetic complications. N En& J Med 318, 1315 5 Clements RS Jr (1979) Diabetic neuropathy-new concepts of its etiology. Diabetes 28, 604 6 Coggeshall JC, Heggers JP, Robson MC, Baker H (1985) Biotin status and plasma glycose in diabetics. Ann NY Acad Sci 447, 389 7 Dyck PJ, Kames JL, O’Brien P, Okazaki H, Lais A, Engelstad J (1986) The spatial distribution of fiber loss in diabetic polyneuropathy suggest ischemia. Ann New-01 19, 440 8 Dyck PJ, Zimmerman BR, Villen TH. Minnerath SR, Kames JL, Yao JK, Poduslo JF (1988) Nerve glucose, fructose, sorbitol, myo-inositol and fiber degeneration and regeneration in diabetic neuropathy. N Engl .I Med 319, 542 9 Asbury AK (1988) Understanding diabetic neuropathy. N Engl J Med 319, 577 10 Greene DA, Latimer SA, Sima AAF (1987) Sorbitol, Phosphoionositides and Sodium-Potasium ATPase in the pathogenesis of diabetic complications. N Engl J Med 316, 599 11 Johnson PC, Doll SC, Cromey DW (1986) Pathogenesis of diabetic neuropathy; Ann Neural 19, 450 12 Krausse K-H, Bonjour J-P, Berlit P, Kohen W (1985) Biotin status in epileptics. Ann NY Acad Sci 447, 297 13 Pate1 MS (1974) The relative significance of COsfixing enzymes in the metabolism of rat brain. J Neurochem 22, 717 14 Porte D Jr, Graf RI, Haltez JB, Pfeifer MA, Halar E (1981) Diabetic neuropathy and plasma glucose control. Am J Med 70, 195
15 Said G, Slama G, Silva J (1983) Progressive centripetal degeneration of axons in small fibre diabetic polyneuropathy. A clinical and pathological study. Brain 106, 791 16 Sima AAF, Bril V, Nathaniel V, Thomas AJ, McEven MS, Brown MB, Lattimer SA, Greene DA (1988) Regeneration and repair of myelinated fibers in sural-nerve biopsy specimens from patients with diabetic neuropathy treated with sorbinil. N EngI J Med 319, 548 17 Sima AAF, Nathaniel V, Bril V, Even TAJ, Greene DA (1988) Histopathological heterogeneity of neuropathy in insulin dependent and non-insulin-dependent diabetics and demonstration of axo-glial dysfunction in human diabetic neuropathy. J Clin Invest 81, 349 18 Thomas PK, Eliason S (1984) Diabetic neuropathy. In: Peripheral neuroparhy. (Dyck PJ, Thomas PK, Lambert EH, Bunge RP, eds) 2nd Ed. Philadelphia: WB Saunders, I 773 19 Thomson PHS, Butterfield WJH, Fry IK (1960) Pyruvate metabolism in diabetic neuropathy. Proc R Sot Med 53, 143 20 Yatzidis H, Koutsikos D, AgI’OyaMiS B, Papastephanidis C, Frances-Plemenos M, Delatola Z (1984) Biotin in the management of Uremic neurologic disorders. Nephron 36, 183 21 Yatzidis H, Koutsikos D, Alaveras AG, Papastephanidis C, Francos-Plemenos M (1981) Biotin for neurologic disorders of uremia. N Eng J Med 305, 764 22 Zundzewitsch RG, Jaspan JB, Polonsky KS, Weinberg GR, Halter JS, Halar E, Pfeifer M, Vukadinovic C, Bernstein L, Schneider M, Liang K, Cabbay KH, Rubinstein AH, Porte D (1983) Aldose reductase inhibition improves nerve conduction velocity in diabetic patients. N Engl J Med 308, 119
